. The leading risk factor for lung cancer in the U.S. is cigarette smoking. The incidence of lung cancer remains alarmingly high and, despite the use of modern diagnostic and treatment modalities, the overall cure rate is low. Thus, preventive efforts, based upon the understanding of risk factors may be of paramount importance in controlling this deadly disease. A minority of smokers develops lung cancer, suggesting variability in disease susceptibility. Smoking itself may contribute to a causal complex along with other contributing factors such as genetic predisposition. Moreover, only a small proportion of all cancers is explained by simple monogenic inheritance. Several polymorphisms in the genes responsible for either activation or deactivation of carcinogens have been reported to be associated with lung cancer risk. To date, however, no studies have had sufficient statistical power to examine a number of complex gene-environment interactions in lung cancer (e.g., dietary and occupational contributions or gene-gene interactions). A large molecular epidemiologic study is proposed to examine six polymorphic traits in metabolism and lung cancer risk and how this risk may be modified by dietary or occupational exposures. The application posits that the combination of traits which enhance activation of carcinogenic metabolites and decrease detoxification of reactive products will confer excess risk in current and former smokers. Furthermore, it suggests that this risk will be modified by diet and occupational exposures. It is intended that a better understanding of these risks and their modification could lead to more effective preventive strategies.